title: Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold.
abstract: A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure-activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Zhang
authors.forename: Minlan
authors.initials: M
authors.lastname: He
authors.forename: Dequan
authors.initials: D
authors.lastname: Gui
authors.forename: Saghir
authors.initials: S
authors.lastname: Hussain
authors.forename: Chaojun
authors.initials: C
authors.lastname: Jing
authors.forename: Changjin
authors.initials: C
authors.lastname: Zhu
authors.forename: Qun
authors.initials: Q
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D013829:Thiadiazines; C559778:pyrido(2,3-e)-(1,2,4)-thiadiazine 1,1-dioxide acetic acid; D000449:Aldehyde Reductase